HIV remains a major public health tragedy and there is currently no effective vaccine. In 2011 an estimated 34 million people were living with HIV and most of the 2.5 million new infections were sexually transmitted. Globally, women make up half those infected with this figure increasing to 59% in sub-Saharan Africa. While male condoms are effective in preventing HIV, negotiating their use can be difficult for women. This need has led to intensive efforts to develop female controlled strategies including vaginally applied microbicides (topical pre-exposure prophylaxis, PrEP) for protection against HIV and other sexually transmitted infections (STIs). In 2010 the CAPRISA 004 trial provided the first proof of concept that a topically applied vaginal gel containing the antiretroviral drug, tenofovir, can be protective. However, the results of subsequent clinical trials with topical and oral antiretroviral based PrEP in women has been mixed. While low adherence is one explanation, biological factors are also being investigated. In this regard, HIV infection via the female reproductive tract is relatively inefficient; however infection with other viral STIs and imbalances in the vaginal microbiome (i.e. bacterial vaginosis, BV) can promote infection. Furthermore, the development of antiretrovirals currently used for therapy in topical and oral PrEP could promote drug resistance. My laboratory has made significant contributions to the preclinical and clinical evaluation of a dendrimer microbicide with broad-spectrum activity against HIV and other viral STIs and in understanding how these molecules block HIV at the molecular level; the characterisation of a potent anti-HIV metabolite produced by lactobacilli found in the vaginal tract that is diminished in women with BV, and in the early discovery of novel HIV reverse transcriptase inhibitors with distinct mechanisms of action to drugs currently used for HIV treatment, for the exclusive use in HIV PrEP.